Tumor heterogeneity and drug-resistance are the leading challenges for cancer immunotherapy. Our goal is to explore the immune surveillance mechanism to develop a broad tumor-recognizing immunotherapy that is self-sustaining and adaptive to tumor evolution. PRELIMINARY RESULTS: We have discovered natural IgM-producing phagocytic B cells (NIMPAB). In mice, L2pB1 cells are the major NIMPAB cells that produce natural IgM antibodies, which are known for their broad-spectrum cancer recognition. Our research has shown that L2pB1 cells can inhibit tumor cell growth and phagocytose apoptotic tumor cells. L2pB1 cells are also the predominant B cells that constitutively express the anti-inflammatory cytokine IL-10 and inducibly express the highest level of IL-10 among all B cells. HYPOTHESIS: We hypothesize that L2pB1 cells have a unique repertoire of broad cancer-recognizing natural IgM antibodies as well as multiple anti-cancer functions. L2pB1 cells might play fundamental roles in cancer immune surveillance through cancer cell recognition, inhibition, antigen presentation and clearance by phagocytosis with tight control of inflammation that prevents tissue damage. Boosting L2pB1 cell number and functions may induce cancer remission and prevent secondary cancer development. APPROACH: To test this, we propose to utilize a combined therapy model using (1) intratumoral injection of L2pB1 cell-attracting chemokines packaged in nanoparticles for controlled release. (2) Adoptive transfer of PtC-liposome expanded L2pB1 cells from self or healthy donors. To facilitate these experiments, we generated a novel knock-in animal model, which allows us to track, monitor and quantify L2pB1 cells in vivo. It also allows inducible depletion of L2pB1 cells at any time. We will inoculate 3 different tumor cell lines in these mice and evaluate tumor inhibition with this combined treatment. NOVELTY: Current immunotherapy strategies utilize the weapons (molecules) and soldiers (cells). Our proposed cancer therapy introduces the commander of our immune surveillance system to establish a sustainable command center with more efficient regulation and adaptation to the heterogeneity of tumors. FUTURE CLINICAL APPLICATION: If we achieve the goals of our study, we would be able to cryopreserve patients' NIMPAB cells before chemotherapy. Alternatively, if some patients are deficient in NIMPAB cells, they could receive a NIMPAB transfer from healthy donors. As NIMPAB can self-renew, a blood bank of NIMPAB can be established from healthy donors or any individual at a young age to use in case the cells are needed when the respective donor becomes older. SIGNIFICANCE: The proposed novel therapy model will significantly advance the cancer immunotherapy field by providing a potential self-renewable therapy for both cancer treatment and cancer prevention. This new therapy addresses the current challenges of lack of sustainability and adaptation to cancer heterogeneity, and will provide a giant leap forward in the cancer immunotherapy field.